CN110981802A - Method for preparing nitrogen-containing heterocyclic compound - Google Patents
Method for preparing nitrogen-containing heterocyclic compound Download PDFInfo
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- CN110981802A CN110981802A CN201911257448.0A CN201911257448A CN110981802A CN 110981802 A CN110981802 A CN 110981802A CN 201911257448 A CN201911257448 A CN 201911257448A CN 110981802 A CN110981802 A CN 110981802A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
Abstract
The invention belongs to the technical field of preparation of nitrogen-containing heterocyclic compounds, and particularly relates to a method for preparing a nitrogen-containing heterocyclic compound. Which comprises the following steps: the method comprises the following steps of carrying out isomerization reaction on raw materials shown in the following formula 1 or 2 under the catalysis of a protonic acid catalyst to respectively and correspondingly prepare nitrogen-containing heterocyclic compounds shown in the formula 3 or 4; the protonic acid catalyst is trifluoromethanesulfonic acid, trifluoromethanesulfonate ester, boron trifluoride-diethyl ether complex or bis (trifluoromethanesulfonyl) imide; the method provided by the invention can be used for preparing the monocyclic or polycyclic nitrogen-containing heterocyclic compound, is simple and easy to operate, does not need metal participation, has wide reaction substrate application range, good regioselectivity and high yield, can be used for quickly synthesizing various types of nitrogen-containing heterocyclic compounds, and has wide application prospect in the preparation of natural products and medicines.
Description
Technical Field
The invention belongs to the technical field of preparation of nitrogen-containing heterocyclic compounds, and particularly relates to a method for preparing a nitrogen-containing heterocyclic compound.
Background
Ketones with nitrogen containing heterocycles are ubiquitous in natural products, pharmaceuticals and biologically active molecules. In recent years, a great deal of effort has been devoted to the synthesis of such nitrogen-containing heterocyclic compounds. Wherein, the cyclization reaction of the eneyne catalyzed by the transition metal can quickly construct carbon-carbon bonds and is widely applied to synthesizing functionalized cyclic compounds. In particular, gold metal catalyzed functionalization of enynenes has been reported in the literature. Because the metal gold catalyst can coordinate with alkyne to activate alkyne structural unit, the active species can perform addition reaction with various nucleophiles.
However, these processes typically require the use of expensive and even toxic noble metal catalysts, relatively harsh reaction conditions, and longer reaction times. Therefore, there is a great need to develop metal-free tandem cyclization of enynes to synthesize functionalized carbocyclic and nitrogen-containing heterocyclic compounds.
Compared with Lewis acid catalysts and transition metal catalysts,
the acid catalyst has the advantages of easier processing, lower price, environmental protection, stability to oxygen and water, and the like.
However, at an early stage of the process,
the application range of the acid catalyst is also relatively limited, and mainly focuses on hydrolysis reaction and esterification reaction. Along with various types of superstrong in recent years
An acid was developed which was able to,
the reaction types in which the acid catalyst participates are greatly broadened.
Now it is
Acid catalysts are commonly used to activate carbonyl, imine, alkene, alkyne, hydroxyl, and form oxonium ions, carbenium ions, and the like.
However, until now, no use for the preparation of heterocyclic ketones has been known.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of a nitrogen-containing heterocyclic compound with a functional group, wherein a catalytic amount of protonic acid is used for activating a pi bond so as to form a new carbon-carbon bond. The reaction condition is mild, and the application range of the substrate is wide.
In order to solve the above problems, the present invention provides the following technical solutions:
a process for preparing a nitrogen-containing heterocyclic compound comprising the steps of:
the method comprises the following steps of carrying out isomerization reaction on raw materials shown in the following formula 1 or 2 under the catalysis of a protonic acid catalyst to respectively and correspondingly prepare nitrogen-containing heterocyclic compounds shown in the formula 3 or 4;
the protonic acid catalyst is trifluoromethanesulfonic acid, trifluoromethanesulfonate ester, boron trifluoride-diethyl ether complex or bis (trifluoromethanesulfonyl) imide;
wherein R1 and R2 are independently selected from substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C1-C10 alkyl;
x is NTs or NMs.
Preferably, the trifluoromethanesulfonate is trimethylsilyl trifluoromethanesulfonate or triethylsilyl trifluoromethanesulfonate.
Preferably, the molar ratio of the protonic acid catalyst to the starting material is from 0.05:1 to 3: 1.
Preferably, the solvent of the isomerization reaction is a non-polar solvent having a dipole moment of 3 to 10.
More preferably at least one of dichloromethane, chloroform and 1, 2-dichloroethane.
Further preferably, the water content in the solvent is 0.05-5%.
Preferably, the concentration of the raw material eneyne is 0.02mmol/mL-0.5 mmol/mL; further preferably 0.03mmol/mL to 0.3 mmol/mL; more preferably 0.05mmol/mL-0.1 mmol/mL.
Preferably, the isomerization reaction time is 1 to 10 hours.
Further preferably 1.5 to 6 hours.
The method for preparing the nitrogen-containing heterocyclic compound has the following beneficial effects:
the method provided by the invention can be used for preparing the monocyclic or polycyclic nitrogen-containing heterocyclic compound, is simple and easy to operate, does not need metal participation, has wide reaction substrate application range, good regioselectivity and high yield, can be used for quickly synthesizing various types of nitrogen-containing heterocyclic compounds, and has wide application prospect in the preparation of natural products and medicines.
Detailed Description
The invention is further illustrated by the following examples. These examples are for illustrative purposes only and do not limit the scope and spirit of the present invention.
Example 1
42.1mg (0.1mmol) of the enyne starting material shown below was charged into a 4mL reaction flask with stirrer, 2mL of wet dichloromethane (water content 1%) was added at room temperature, 0.4uL (0.01mmol) of trifluoromethanesulfonic acid was added, stirred at room temperature for 2 hours, spun dry and isolated by preparative thin layer chromatography to give the desired product in 66% yield.
The detection results of the target products are as follows:
1H NMR(400MHz,CDCl3)δ7.85–7.80(m,2H),7.67(d,J＝8.3Hz,2H),7.57–7.51(m,1H),7.44(dd,J＝10.5,4.7Hz,2H),7.29(t,J＝6.7Hz,2H),3.72–3.65(m,2H),3.22(dd,J＝4.7,2.0Hz,1H),3.11(dd,J＝12.9,4.8Hz,1H),2.62–2.53(m,2H),2.43(s,3H),1.59–1.53(m,1H),1.47(dd,J＝12.6,3.1Hz,1H),1.37(ddd,J＝13.4,10.6,5.7Hz,2H),1.31–1.22(m,2H),1.11(s,3H),0.95(s,3H),0.81(s,3H).
13C NMR(101MHz,CDCl3)δ200.47,143.38,138.36,134.54,132.95,129.66,128.77,128.15,127.82,51.57,44.21,43.15,42.33,41.66,36.50,36.28,33.02,32.49,22.26,21.69,21.04,18.58.
HR-MALDI-MS m/z calcd.forC26H33NNaO3S[M+Na]+:462.2073,found:462.2073.
example 2
43.5mg (0.1mmol) of the enyne substrate shown below were charged into a 4mL reaction flask with stirrer, 2mL of wet dichloromethane (water content 1%) were added at room temperature, 0.4uL (0.01mmol) of trifluoromethanesulfonic acid were added, stirred at room temperature for 2 hours, spun dry and isolated by preparative thin layer chromatography to give the desired product in 68% yield.
The detection results of the target products are as follows:
1H NMR(400MHz,CDCl3)δ7.73(d,J＝8.2Hz,2H),7.67(d,J＝8.3Hz,2H),7.29(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,2H),3.71–3.60(m,2H),3.20(dd,J＝4.7,2.1Hz,1H),3.11(dd,J＝12.9,4.7Hz,1H),2.69–2.53(m,2H),2.42(s,3H),2.40(s,3H),1.62–1.50(m,1H),1.45(dd,J＝12.6,3.2Hz,1H),1.41–1.32(m,2H),1.30–1.20(m,2H),1.11(s,3H),0.94(s,3H),0.80(s,3H).
13C NMR(101MHz,CDCl3)δ200.06,143.75,143.33,135.85,134.64,129.64,129.45,128.32,127.84,51.38,44.17,43.22,42.33,41.68,36.54,36.25,33.02,32.50,22.27,21.71,21.69,21.09,18.59.
HR-MALDI-MS m/z calcd.forC27H35NNaO3S[M+Na]+:476.2230,found:476.2228.
example 3
44.0mg (0.1mmol) of the enyne substrate shown below were charged into a 4mL reaction flask with stirrer, 2mL of wet dichloromethane (water content 1%) were added at room temperature, 0.4uL (0.01mmol) of trifluoromethanesulfonic acid were added, stirred at room temperature for 2 hours, spun dry and isolated by preparative thin layer chromatography to give the desired product in 64% yield.
1H NMR(400MHz,CDCl3)δ7.86(ddd,J＝8.3,5.2,2.5Hz,2H),7.67(d,J＝8.2Hz,2H),7.30(d,J＝7.9Hz,2H),7.16–7.06(m,2H),3.70–3.60(m,2H),3.16(dd,J＝4.6,1.9Hz,1H),3.12–3.05(m,1H),2.62–2.50(m,2H),2.43(s,3H),1.64–1.56(m,2H),1.46–1.36(m,2H),1.30–1.21(m,2H),1.11(s,3H),0.95(s,3H),0.81(s,3H).
13C NMR(101MHz,CDCl3)δ198.80,166.98,164.33,143.43,134.65(d,J＝17.4Hz),130.79(d,J＝9.2Hz),129.68,127.80,115.85(d,J＝21.8Hz),51.60,44.23,43.19,42.34,41.65,36.55,36.34,33.03,32.50,22.26,21.69,21.07,18.58.
19F NMR(377MHz,CDCl3)δ-105.69.
HR-MALDI-MS m/z calcd.forC26H32FNNaO3S[M+Na]+:480.1979,found:480.1976.
Example 4
47.9mg (0.1mmol) of the enyne substrate shown below were charged into a 4mL reaction flask with stirrer, 2mL of wet dichloromethane (water content 1%) were added at room temperature, 0.4uL (0.01mmol) of trifluoromethanesulfonic acid were added, stirred at room temperature for 2 hours, spun dry and isolated by preparative thin layer chromatography to give the desired product in 63% yield.
1H NMR(400MHz,CDCl3)δ8.15–8.06(m,2H),7.90–7.81(m,21H),7.69–7.63(m,2H),7.29(d,J＝8.0Hz,2H),3.95(s,3H),3.72–3.63(m,2H),3.19(dd,J＝4.6,2.0Hz,1H),3.09(dd,J＝12.8,4.7Hz,1H),2.60–2.52(m,2H),2.43(s,3H),1.64–1.59(m,2H),1.49–1.39(m,2H),1.27(ddd,J＝15.5,11.7,3.5Hz,2H),1.11(s,3H),0.96(s,3H),0.80(s,3H).
13C NMR(101MHz,CDCl3)δ200.06,166.34,143.48,141.74,134.54,133.71,130.04,129.71,128.02,127.79,52.62,52.23,44.32,43.09,42.35,41.66,36.52,36.43,33.03,32.51,22.25,21.69,21.01,18.58.
HR-MALDI-MS m/z calcd.forC28H35NNaO5S[M+Na]+:520.2128,found:520.2128.
Example 5
33.9mg (0.1mmol) of the enyne substrate shown below were charged into a 4mL reaction flask with stirrer, 2mL of wet dichloromethane (water content 1%) were added at room temperature, 0.4uL (0.01mmol) of trifluoromethanesulfonic acid were added, stirred at room temperature for 2 hours, spun dry and isolated by preparative thin layer chromatography to give the desired product in 71% yield.
1H NMR(400MHz,CDCl3)δ7.78–7.68(m,4H),7.54–7.47(m,1H),7.43–7.36(m,2H),7.29(d,J＝7.9Hz,2H),3.73(t,J＝7.6Hz,1H),3.60(ddd,J＝28.4,10.0,7.6Hz,2H),3.16(d,J＝9.5Hz,1H),3.04(d,J＝9.5Hz,1H),2.39(s,3H),1.04(s,3H),0.62(s,3H).
13C NMR(101MHz,CDCl3)δ199.14,143.62,137.84,133.98,133.61,129.83,128.87,128.47,127.75,61.04,53.19,49.73,42.52,27.64,22.44,21.74.
HR-MALDI-MS m/z calcd.forC20H23NNaO3S[M+Na]+:380.1291,found:380.1289.
Example 6
40.1mg (0.1mmol) of the enyne substrate shown below were charged into a 4mL reaction flask with stirrer, 2mL of wet dichloromethane (water content 1%) were added at room temperature, 0.4uL (0.01mmol) of trifluoromethanesulfonic acid were added, stirred at room temperature for 2 hours, spun dry and isolated by preparative thin layer chromatography to give the desired product in 61% yield.
1H NMR(400MHz,CDCl3)δ7.79–7.73(m,2H),7.58–7.46(m,3H),7.38–7.30(m,4H),7.11–7.03(m,3H),6.95–6.88(m,2H),4.18(dd,J＝7.7,3.2Hz,1H),4.11–4.03(m,1H),3.91(dd,J＝10.7,7.7Hz,1H),3.70(d,J＝8.7Hz,1H),3.55(dt,J＝16.2,8.1Hz,1H),2.44(s,3H),1.47(s,3H).
13C NMR(101MHz,CDCl3)δ199.43,143.62,143.12,137.33,134.25,133.24,129.86,128.67,128.44,128.09,127.64,126.64,125.91,57.88,53.41,50.16,50.05,30.08,21.73.
HR-MALDI-MS m/z calcd.forC25H25NNaO3S[M+Na]+:442.1447,found:442.1447。
The above examples are for illustrative purposes only and the scope of the present invention is not limited thereto. Modifications will be apparent to those skilled in the art and the invention is limited only by the scope of the appended claims.
Claims (10)
1. A process for preparing a nitrogen-containing heterocyclic compound comprising the steps of:
the method comprises the following steps of carrying out isomerization reaction on raw materials shown in the following formula 1 or 2 under the catalysis of a protonic acid catalyst to respectively and correspondingly prepare nitrogen-containing heterocyclic compounds shown in the formula 3 or 4;
the protonic acid catalyst is trifluoromethanesulfonic acid, trifluoromethanesulfonate ester, boron trifluoride-diethyl ether complex or bis (trifluoromethanesulfonyl) imide;
wherein R1 and R2 are independently selected from substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C1-C10 alkyl;
x is NTs or NMs group.
2. The method of claim 1, wherein the trifluoromethanesulfonate is trimethylsilyl trifluoromethanesulfonate or triethylsilyl trifluoromethanesulfonate.
3. The process of claim 1, wherein the molar ratio of protic acid catalyst to starting material is from 0.05:1 to 3: 1.
4. The process of claim 1, wherein the concentration of starting enyne is from 0.02mmol/mL to 0.5 mmol/mL.
5. The process according to claim 1, wherein the isomerization reaction time is 1 to 10 hours.
6. The process according to claim 5, wherein the isomerization reaction time is 1.5 to 6 hours.
7. The process of claim 1, wherein the solvent for the isomerization reaction is a non-polar solvent having a dipole moment of 3-10.
8. The process of claim 7, wherein the solvent for the isomerization reaction is at least one of dichloromethane, trichloromethane, and 1, 2-dichloroethane.
9. The method of claim 8, wherein the solvent has a water content of 0.05-5%.
10. The process of claim 8, wherein the isomerization solvent is methylene chloride.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111592481A (en) * | 2020-06-03 | 2020-08-28 | 江南大学 | Preparation method of polysubstituted pyrroline compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804283A (en) * | 2012-11-06 | 2014-05-21 | 中国科学院大连化学物理研究所 | Preparation method for 1, 2-dihydropyridine derivative |
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| CN103804283A (en) * | 2012-11-06 | 2014-05-21 | 中国科学院大连化学物理研究所 | Preparation method for 1, 2-dihydropyridine derivative |
Non-Patent Citations (2)
| Title |
|---|
| TIENAN JIN ET AL.: "Triflic acid-catalyzed cascade cyclization of arenyl enynes via acetylene-cation cyclization and Friedel–Crafts type reaction", 《TETRAHEDRON LETTERS》 * |
| ZHUNZHUN YU ET AL.: "Triflic Acid-Catalyzed Enynes Cyclization:A New Strategy beyond Electrophilic π-Activation", 《 CHEM.EUR.J.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111592481A (en) * | 2020-06-03 | 2020-08-28 | 江南大学 | Preparation method of polysubstituted pyrroline compound |
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